Ophthalmic Drug Delivery Systems

Ophthalmic Drug Delivery Systems for the Treatment ofRetinal Diseases: Basic Research to Clinical Applications

Henry F. Edelhauser,1 Cheryl L. Rowe-Rendleman,2 Michael R. Robinson,3

Daniel G. Dawson,1 Gerald J. Chader,4 Hans E. Grossniklaus,1 Kay D. Rittenhouse,5

Clive G. Wilson,6 David A. Weber,7 Baruch D. Kuppermann,8 Karl G. Csaky,9

Timothy W. Olsen,1 Uday B. Kompella,10 V. Michael Holers,11 Gregory S. Hageman,12,13

Brian C. Gilger,14 Peter A. Campochiaro,15 Scott M. Whitcup,3 and Wai T. Wong16

The ARVO 2009 Summer Eye Research Conference (SERC2009) on Ophthalmic Drug Delivery Systems was held July

31 and August 1, 2009, at the National Institutes of Health(NIH) in Bethesda, Maryland. The conference provided anopportunity to gather a diverse group of more than 200 ex-perts from both academic ophthalmology and the ophthalmicpharmaceutical industry, including laboratory researchers and

clinicians, to discuss recent advances in delivery systems thatconvey ocular drugs to the posterior segment and how thesesystems might be successfully used in commercial products.

The two-day meeting comprised the following nine ses-sions: (1) eye anatomy and ocular barriers to drug transport, (2)the vitreous humor in drug delivery, (3) intravitreal drug de-livery, (4) transscleral drug delivery for retinal diseases, (5)preclinical benchmarks for retinal drug therapy, (6) animalmodels for evaluating drug delivery systems, (7) topical ther-apy for retinal diseases, (8) clinical trials, and (9) new data fromabstracts.

This meeting was co-sponsored by the Association in Re-search in Vision and Ophthalmology (ARVO) and the NIH toexpand and continue ongoing collaborative interchange andsynergic endeavors that were addressed at an earlier confer-ence, held May 4 and 5, 2007, and sponsored by the PfizerOphthalmics Research Institute Conference.1 SERC 2009 wasorganized by Cheryl L. Rowe-Rendleman, PhD (Omar Consult-ing Group, LLC), Michael R. Robinson, MD (Allergan Inc.), andHenry F. Edelhauser, PhD (Emory University). Edelhauser andPaul A. Sieving, MD, PhD, started off the meeting with intro-ductory comments.

Edelhauser began by briefly discussing the history of basicscience research involving ophthalmic drug delivery. Hetouched on the difficulty in finding a flawless technique todeliver drugs targeting diseases that directly affect the retinaand vitreous humor, owing to the anatomic barriers and phys-iologic clearance mechanisms of the blood–neural barriers(BNBs). The BNBs comprise the blood–retinal barrier (BRB)posteriorly and the blood–aqueous barrier (BAB) anteriorly(Fig. 1). He also mentioned the importance of the transcellularand paracellular transport pathways across or between epithe-lial or endothelial BRBs (Fig. 2). Edelhauser described thepurpose of SERC 2009, designed as a forum in which research-ers and clinicians could have an open dialog about their work,during and between meeting sessions, all in the service ofadvancing the field of ophthalmology.

Sieving, director of the National Eye Institute (NEI), out-lined the major ophthalmic blinding diseases in the UnitedStates and their pathophysiologies, pointing out their eco-nomic costs to society. In conclusion, he noted that, manytimes, the most crucial step in successfully translating promis-ing drugs from the bench to the bedside is identifying the bestdrug delivery route.

Given the emphasis on translational science and the non-synchronized arrangement of lectures and posters, this sum-mary of SERC 2009 presents the major topics of the meeting bytheme, not necessarily in the order of their original presenta-tion. Each lecture has been included in the material for thepertinent area of study (see meeting agenda in the Supplemen-

From the 1Department of Ophthalmology, Emory University, At-lanta, Georgia; 2Omar Consulting Group, Princeton Junction, NewJersey; 3Allergan Inc., Irvine, California; the 4Doheny Eye Institute,Keck School of Medicine, University of Southern California, Los Ange-les, California; 5Pfizer, La Jolla, California; the 6Department of Pharma-ceutical Sciences, University of Strathclyde, Glasgow, Scotland; 7Macu-Sight, Union City, California; the 8Gavin Herbert Eye Institute,University of California-Irvine Medical School, Irvine, California; the9Department of Ophthalmology, Duke University School of Medicine,Durham, North Carolina; the 10Department of Pharmaceutical Sci-ences, University of Colorado-Denver, Aurora, Colorado; 11TaligenTherapeutics, Boston, Massachusetts; the 12Department of Ophthal-mology and Visual Sciences, Cell Biology and Functional GenomicsLaboratory, The University of Iowa, Iowa City, Iowa; the 14Departmentof Clinical Sciences, North Carolina State University, College of Veter-inary Medicine, Raleigh, North Carolina; 15Wilmer Eye Institute, JohnsHopkins University, Baltimore, Maryland; and the 16National Eye Insti-tute, National Institutes of Health, Bethesda, Maryland.

13Present affiliation: John Moran Eye Center, University of UtahHealth Science Center, Salt Lake City, Utah.

Supported by NIH Core Grant 5P30EY006360-23 (HFE, HEG,TWO), NIH Grant SR24 EY017045 (HFE, HEG, UBK), and NIH GrantR24 EY017404 (GSH); the Alcon Research Institute (GSH); and anunrestricted grant from Research to Prevent Blindness (TWO).

Submitted for publication February 16, 2009; revised March 27and April 29, 2010; accepted April 30, 2010.

Disclosure: H.F. Edelhauser, Alcon (C); C.L. Rowe-Rendleman,Omar Consulting (E), Taligen Therapeutics (C); M.R. Robinson, Al-lergan (E); D.G. Dawson, None; G.J. Chader, None; H.E. Grossni-klaus, None; K.D. Rittenhouse, Pfizer (E); C.G. Wilson, None; D.A.Weber, MacuSight (E); B.D. Kuppermann, Allergan (F, C), Alimera(F), Genentech (F, C), NeoVista (F), Novagali (F), Optherion (F),Renegeneron (F), Thrombogenics (F); Braun (C), CoMentis (C), Fovea(C), Glaukos (C), Novartis (C), Ophthotech (C), Pfizer (C), ScyFix (C),Surmodics (C), TargeGen (C), VitreoRetinal Technologies (C); K.G.Csaky, Ophthotech (I), Potentia (I); Allergan (C), Genentech (C),GlaxoSmithKline (C), Heidelberg Engineering (C), Novartis (C); T.W.Olsen, None; U.B. Kompella, Allergan (F, C); V.M. Holers, TaligenTherapeutics (I, E, P); G.S. Hageman, Optherion (I); B.C. Gilger,None; P.A. Campochiaro, Alcon (F), Alimera (F), CoMentis (F), Targe-Gen (F), Genentech (F, C), GlaxoSmithKline (C), Regeneron (C); S.M.Whitcup, Allergan (E); W.T. Wong, None

Corresponding author: Henry F. Edelhauser, Department of Oph-thalmology, Emory University Eye Center, 1365B Clifton Road, Atlanta,GA 30322; [email protected].

Research Opportunities

DOI:10.1167/iovs.10-5392Investigative Ophthalmology & Visual Science, November 2010, Vol. 51, No. 11Copyright © Association for Research in Vision and Ophthalmology

5403

tary Material, http://www.iovs.org/cgi/content/full/51/11/5403/DC1).

The basic science part of this article focuses on the ana-tomic barriers to the five major modes of ocular drug delivery:intraocular, periocular, hybrid, topical, and systemic. The sec-ond half is a review of the clinical and regulatory componentsof translational science.

TREATMENTS AND UNMET NEEDS

Gerald J. Chader, PhD, provided an overview of the steps thatscientists in industry and academia are taking to finding newophthalmic treatments and what he believes to be the basickeys to success in translational research. He declared thatcorrectly assessing the major unmet needs in the treatment ofophthalmic diseases is the first step in moving from the benchto the bedside. Subsequently, a series of steps are needed todevelop and clinically implement a safe and effective newtreatment, be it a drug, device, or procedure.

Chader then summarized the current state-of-the-art tech-nology that is being used to treat some major posterior seg-

ment diseases, noting that diseases sharing a locus may havedifferent unmet needs.

Combined Anterior and PosteriorSegment Diseases

Endophthalmitis, uveitis, and glaucoma are common combinedanterior and posterior segment diseases, but each presents adifferent unmet need. For endophthalmitis, the unmet need isprevention. When prevention fails, treatment is most effec-tively performed with prompt intravitreal and subconjunctivalantibiotics, with or without vitrectomy and systemic antibiot-ics. For uveitis, good short-term control of the disease can beobtained with topical, periocular, or systemic anti-inflamma-tory or immunosuppressive drugs (e.g., corticosteroids). Themajor unmet need involves the treatment of chronic or recur-rent uveitic disease, because long-term treatment with theseagents commonly results in toxicity and complications due tocumulative dose-related side effects, such as cataract and glau-coma. Finally, for glaucoma, although fair to adequate controlof intraocular pressure can be obtained with topical drugs andvarious anterior segment procedures and surgeries, a treatment

FIGURE 1. Diagram of the brain andspinal cord illustrating how the eye’sinner and outer blood-retinal barriers(BRBs) fit into the overall scheme ofblood-neural barriers (BNBs). Barriersbetween the blood and neural tissuesare collectively referred to as BNBs andinclude the blood-brain barrier (A), theblood-CSF barrier (B), the BRB (C), andthe blood-spinal cord barrier (D).Other similar specialized barriers inthe body include the blood-labyrinthbarrier in the inner ear, the blood-nerve barrier in the peripheral nervoussystem, and the blood-testis barrier.Their function is to act as semiperme-able paracellular passive diffusion bar-riers or gates to large and hydrophilicsolutes. Small, lipophilic essential nu-trients and toxic metabolites are deliv-ered or removed, respectively,through passive or active site-specifictranscellular carrier–mediated influxor efflux transporters. Considering thatseveral retinal disorders are accompa-nied by dysfunction or breakdown ofthis BRB and their associated cell-cellsignaling mechanisms, elucidating thenature of the BRB is important for un-derstanding normal health and disease.The static morphologic structure re-sponsible for all these organ-specificbarriers is the tight junction (TJ).Counterintuitively, curative drug ther-apy to these protected sites requiresthat drugs circumvent these naturallyprotective barriers. Reprinted withpermission from Choi YK, Kim KW.Blood-neural barrier: its diversity andcoordinated cell-to-cell communica-tion. BMB Rep. 2008;41:345–352.

5404 Edelhauser et al. IOVS, November 2010, Vol. 51, No. 11

for optic nerve or ganglion cell neurodegeneration is stilllargely unavailable.

Posterior Segment Diseases

Concerning strictly posterior segment diseases, the two majorblinding diseases in the United States are diabetic retinopathy(DR) and age-related macular degeneration (AMD). DR is the

main cause of irreversible blindness in adults aged 20 to 65years, with incidence rates of 56% for nonproliferative DR and29% for proliferative DR. Macular edema (ME) occurs in ap-proximately 10% of diabetics. AMD is the main cause of irre-versible blindness in adults older than 65 years. The prevalenceof all forms of AMD in the 65- to 74-year age group is 20%, andit is closer to 35% in older age groups.2

Degenerative Diseases

The two other classes of visually significant retinal diseasesdiscussed at SERC 2009 were degenerative and tumorigenicdiseases: retinitis pigmentosa, Leber’s congenital amaurosis,and the chorioretinal tumors, which include retinoblastoma,choroidal melanoma, and intraocular lymphoma.

In some patients with DR, the sequelae of retinopathicdisease may be partially preventable or slowed down withproper diet, weight management, and intensive blood glucosecontrol with systemic medications, such as insulin or oralhypoglycemic agents. Despite efforts at prevention, DR re-mains a chronic disease with a high prevalence rate amongpeople with diabetes. When DR progresses to the point ofbecoming a vision-threatening complication, laser photocoag-ulation and vitreous surgery are only modestly effective inrecovering or maintaining visual potential. The recent ad-vances in the development of new therapeutic agents, such asintravitreal drugs (e.g., steroids or anti-vascular endothelialgrowth factor), also have been helpful, but more effectiveagents are still greatly needed.

For AMD, although oral antioxidants in the form used in theAge-Related Eye Disease Study can modestly reduce the pro-gression rate at some stages of dry AMD, it was emphasizedthat no truly effective treatment is currently available for pa-tients with advanced disease. In contrast, for wet AMD, intra-vitreally delivered drugs that target vascular endothelial growthfactor, such as ranibizumab (Lucentis; Genentech, South SanFrancisco, CA) and bevacizumab (Avastin; Genentech), can beeffective in stabilizing vision in the short term, although theireffectiveness in the long term is still unclear. Monthly injec-tions of anti-VEGF therapies to maximize visual potential are asignificant treatment burden on the patient. As a result, theneed for better treatments for AMD remains.

Chronic retinal degenerative diseases such as retinitis pig-mentosa continue to lack effective treatment, as current op-tions are either minimally effective (vitamin A) or are still underinvestigation in animal models (ribozyme techniques). How-ever, treatment of a specific type of retinal degeneration,Leber’s congenital amaurosis, recently has taken a large leapforward. It is the first successful human gene therapy in whicha specific disease-causing mutation is replaced in the retina viaan adenovirus-associated delivery system.

Tumors

Hans E. Grossniklaus, MD, and A. Linn Murphree, MD, dis-cussed the current treatments for tumors and the related un-met needs. We are still in need of new treatment options forchorioretinal tumors, such as choroidal melanoma, since suchconventional treatments as enucleation and/or local plaqueradiation brachytherapy do not significantly improve long-termsurvival due to indolent micrometastatic disease, most com-monly involving the liver. Although current local treatmentsare good, there is room for improvement. Similarly, intraocularlymphoma treatment must receive more consideration, as theprognosis is poor with current conventional treatments, pri-marily owing to the disease’s origins in the central nervoussystem.

Although retinoblastoma has some fairly effective local andsystemic treatment options, such as cryotherapy, chemoreduc-

Transcellular routeApical side

Basal side

Apical side

Occludin

Claudins

Tricellulin

JAM

Basal side

Paracellular route

Tight junction(TJ)

Transporter

Simple diffusion

Receptor

FIGURE 2. Diagram of the transcellular and paracellular transportpathways across or between epithelial or endothelial BRBs of theposterior segment. Tight junctions (TJs) are the most apical compo-nent of both the epithelial or endothelial intercellular junctional com-plexes. TJs are crucial for the formation and maintenance of epithelialand endothelial paracellular barriers since they semipermeably regu-late intercellular passive diffusion of large or hydrophilic ions andsolutes. Moreover, a complex network of TJ proteins have been iden-tified, with the assembly and dynamic maintenance of various claudinproteins being the most crucial in regard to dictating the selectivity ofthis paracellular barrier. Using the transcellular route, drugs are deliv-ered by simple passive diffusion to bind with cell surface membrane–bound transporters (cell surface receptors, pumps, channels, and trans-porters) where they can directly cross the cell via passive diffusionagain or through active transport mechanisms. Various influx andefflux transporters have been found for small lipophilic peptides,organic anions, and cations. Transporter-mediated drug delivery istissue-specific and has low toxicity since transmembrane concentra-tion gradients are not required for it work. The transcellular pathwayis not suitable for high-throughput production of drug candidatesthough, unlike the paracellular pathway, which is suitable for high-throughput production since drug modification is not needed and onemethod can be applied for various drugs. Knowing the rate-limitingtissue barrier based on the physiochemical properties of a drug helpswhen optimizing the absorption of passively penetrated drugs. Re-printed with permission from Matsuhisa K, Kondoh M, Takahashi A,Yagi K. Tight junction modulator and drug delivery. Expert Opin DrugDeliv. 2009;6:509–515.

IOVS, November 2010, Vol. 51, No. 11 Drug Delivery Systems for Retinal Diseases 5405

tion and, sometimes, periocular chemotherapy, enucleation isstill frequently used in patients with advanced disease. Intra-arterial chemotherapeutic drug delivery, however, is an excit-ing new treatment option that looks promising for the treat-ment of late-stage retinoblastoma, for which enucleation wasformerly the only viable option. However, the long-term mor-bidity of this disease still makes prevention through geneticscreening or possibly gene therapy the preferred goal.

IDENTIFYING AND OVERCOMING BARRIERS TO

NEW TREATMENTS

Chader then discussed the barriers to and challenges in devel-oping and implementing safe and effective new treatmentoptions in the clinic. He identified five key barriers: (1) devel-oping an effective product, (2) identifying and implementingthe best method of delivery, (3) using the appropriate animalmodel for testing the drug’s safety and efficacy, (4) identifyingan adequate patient sample and developing a well-consideredtreatment design or plan for a clinical trial to attain a satisfac-tory endpoint, and (5) locating a company to finance theproduct and guide it into the commercial market.

Chader then touched on factors that are of paramountimportance in having a successful product or drug. First, thedrug must be safe for the patient over the short and long term.Second, the drug must have adequate bioavailability to reachthe targeted tissues in therapeutic concentrations levels—thatis, the delivered therapeutic agent must reach the back of theeye in sufficient concentrations, do so in a timely manner, andremain there long enough to maintain the necessary therapeu-tic effect. Third, the timing of the product’s launch on thecommercial market is important, because the first product onthe market, even if only mildly effective, typically remainsquite successful until a better product emerges. Fourth, theearlier in the disease’s evolution that the intervention can beintroduced, the higher is its potential for overall effectivenessin preventing or slowing the disease process. Finally, if twodrugs are roughly equal in their safety and efficacy, the drugthat is easier to deliver, is tolerated better, and enables greaterpatient adherence to the regimen is likely to dominate themarket. Chader mentioned that without a successful and con-venient drug delivery system, drugs that are very effective atthe bench or in preclinical testing often fail clinically.

MARKET POTENTIAL

Chader stated that the main driving force for translationalresearch is the commercial ophthalmic market, in which U.S.consumers spent $10 billion in 2007 and are predicted tospend $14 billion in 2009.3 The ultimate marker of success iswhether the treatment makes it to the clinic and therebybecomes available to treat illness.

Chader emphasized the growth potential in this largelyuntapped market: 55% of all debilitating ocular diseases areposterior segment diseases, yet only 5% of ophthalmic phar-maceutical sales in 2007 were for treating posterior segmentdiseases.3 Moreover, the predictions of the future prevalencerates of posterior segment diseases issued in epidemiologicstudies should also be considered: increasing aging of popula-tions throughout the United States and the world, paired withother factors, including an increase in the prevalence of age-related diseases and sedentary lifestyles, will ultimately lead toa far greater worldwide prevalence of many diverse ophthal-mic diseases, in addition to those related to only aging andobesity (Fig. 3).3 Chader also raised a very important socialconsideration: after cancer, Americans fear blindness most.4

He concluded by mentioning a financial consideration thatshould interest both the U.S. federal government and the oph-thalmic health care industry: Blindness and irreversible sightimpairment cost an estimated $50 billion each year in theUnited States and, thus, improving on the treatments availabletoday could substantially reduce the financial burden on soci-ety.3 Chader hastened to emphasize that improvements in drugdiscovery and delivery will not help all blind people.

UNDERSTANDING EYE DISEASES’ PATHOGENESES

AND PATHOPHYSIOLOGIES

In subsequent talks, Grossniklaus illustrated that an importantstep in helping to develop successful treatments for ophthal-mic diseases is first to understand the pathogenesis or patho-physiology of these major ophthalmic diseases. These aspectsare oftentimes best understood through evaluation of the clin-icopathologic correlations of their disease-causing mecha-nisms. Although disease origins are beyond the scope of thisarticle, the current understanding of the causative processesinvolved are inflammation and immunology (observed in dryand wet AMD), neovascularization (DR and wet AMD), agingand oxidative damage (dry and wet AMD), and genetic muta-tions (e.g., retinal degenerations, retinoblastoma, choroidalmelanoma, and intraocular lymphoma) (Fig. 4).

Since the main theme of SERC 2009 was centered on pos-terior segment drug delivery, many presenters described basicdrug delivery concepts, including anatomic barriers and phys-iological clearance mechanisms. The treatment of retinal dis-eases is challenging, since the same anatomic, physiologic, andimmune properties that effectively protect and nourish thehealthy eye also hinder the efficient absorption of pharmaceu-tical drugs. Routes of drug administration that are currentlyused in the clinical setting to treat posterior segment diseasesare the intraocular (i.e., intravitreal injection) and periocular(i.e., sub-Tenon’s injection) routes (Fig. 5).5

Intraocular Drug Delivery

Intraocular drug delivery is the only mode that currently di-rectly broaches the BRB and thereby attains the highest peakintravitreal or intraretinal drug concentrations. Therefore, com-

FIGURE 3. Factors identified in epidemiologic studies as predictors offuture prevalence rates of posterior segment diseases.


pared with the other drug delivery routes, it achieves thehighest intraocular bioavailability in posterior segment tissues(Table 1) such as the cone-containing macula or fovea.1,6,7

However, intraocular drug delivery is the most invasive, in thatit involves penetrating the globe and thus is not free of injec-tion-related complications. These complications may includeraised IOP, floaters, vitreous hemorrhage, transient blurry vi-sion, retinal hemorrhage, retinal tears, retinal detachment, en-dophthalmitis, and cataracts—with rates of endophthalmitisand retinal detachment per injection reaching 0.2% and 0.05%,respectively.8,9 In his poster presentation at SERC 2009, DanielRoth, MD, suggested using superior rather than inferior injec-tions, owing to the lower associated rates of endophthalmitis(0.01%, versus 0.2% for inferior injection; P � 0.011) (Roth DB,et al. IOVS 2009;50:ARVO E-Abstract 3566).

Moreover, the presence of some moderate clearance mech-anisms (posterior transretinal and anterior aqueous humorelimination pathways) cause the peak drug concentration lev-els achieved with intraocular administration to decline to non-therapeutic trough levels over time, unless the injections aregiven frequently and repeatedly, which imposes a significanttreatment burden on the patient, a high clinical burden onophthalmic health care providers, and a cumulative risk ofadverse effects from each subsequent injection.1,6,7,10

The disadvantage caused by the short to medium durationof action of intravitreal drug solutions (Table 1) has beenpartially alleviated through product formulation (e.g., drugphysiochemical changes, suspensions, free-floating or scleral-fixated intravitreal biodegradable implants, and biodegradablemicro- or nanoparticles) or drug device development (e.g.,free-floating or scleral-fixated, nondegradable intravitreal im-plants or nondegradable micro- or nanopaticles). Because im-

plant devices are associated with risks and complications re-lated to surgical placement and long-term drug exposure, theymay be best suited for the treatment of chronic conditions thatrequire extended drug therapy.

Overall, when compared with other modalities, intravitrealinjection, and implantation may be the best in terms of efficacyand the worst in terms of safety (Table 1). Currently, despite itsshortcomings, intravitreal administration is the preferred drugdelivery route to treat diseases of the posterior segment.1,6–8

Static Anatomic Permeability Barriers. Several tissues inthe eye are generally regarded as static and have been consid-ered in the past as simple diffusive barriers. To understand thepharmacokinetics of intravitreal drug delivery better, it wasrepeatedly emphasized in several SERC 2009 lectures, includ-ing that of Clive G. Wilson, PhD, that it is important to under-stand the molecular structure of the normal human vitreous geland that normal vitreous gel undergoes age-related degenera-tive liquefaction. How age-related changes affect the distribu-tion and clearance of drugs after intravitreal administration isan area of active research. The breakdown of the spacingelements of the heterotypic collagen fibrils and the loss ofsurface type IX collagen molecules results in the aggregation offibrils in some parts of the vitreous and the loss of collagenfibrils in other parts, which is then converted into liquidvitreous.11

At infancy, 100% of a human’s vitreous is in the gel phaseand 0% is in the liquid phase, whereas in senescence, 49% is inthe gel phase and 51% is in the liquid phase.11 The age-relatedliquefaction process does not occur uniformly within the vit-reous cavity; pockets of liquid vitreous (where intravitrealdrugs can collect) form in the central vitreous, where theyenlarge and coalesce.11,12 Eventually, the vitreous liquefaction

FIGURE 4. Diagram of acute andchronic ocular immune inflamma-tion. Acute inflammation is initiatedby associated tissue damage and by anaïve cellular immune responsethrough immature antigen present-ing cells in the eye. This results in thesubsequent recruitment of acute-phase inflammation cells from theconjunctival and episcleral bloodvessels. In contrast, chronic immuneinflammation involves procurementand processing of antigens by matureantigen presenting cells in the eyethat migrate to the local afferent armof the lymph drainage system in theconjunctiva, where antigen-APCsdrain into regional lymph nodes andthe spleen. This then results in aprimed T-cell response that migratesout of the lymph system back intothe eye via the blood vessels in theeye, including conjunctival and epis-cleral blood vessels. The cells adhereto vascular endothelium and enterthe tissue through diapedesis. APCsindicate antigen presenting cells;CPIs, corneal proteases; DC, den-dritic cells; TNF-�, tumor necrosisfactor alpha; IL-6, interleukin 6;IFN-�, interferon gamma. Reprintedwith permission from McDermottAM, Perez V, Huang AJW, et al. Path-ways of corneal and ocular surfaceinflammation: a perspective from theCullen symposium. Ocul Surf. 2005;3:S131–S138. Artist: Elaine Kurie.


combined with age-related weakening of postbasal vitreoreti-nal adhesions predisposes elderly individuals to posterior vit-reous detachment (PVD), in which the cortical vitreous gelsplits away from the inner limiting lamina of the retina, usuallyextending as far anteriorly as the posterior border of the vitre-ous base.

PVDs can be localized, partial, or complete. Typically dur-ing initiation of a PVD, the residual vitreous body collapses,and the liquefied vitreous leaks through a hole in the posteriorcortical vitreous, which then helps dissect the residual poste-rior cortical vitreous from the retina.12 During the evolution ofa PVD, separation of the posterior cortical vitreous from theperipheral retina at the vitreous base does not occur, becauseof the strong perpendicular adhesion of vitreal collagen fibrilswithin the superficial retina.11,12

PVD occurs spontaneously, with a lifetime occurrence rateof approximately 25%.11,12 Normal vitreous humor has a dis-continuity only in the cortical vitreous at the optic nerve and isthinned over the macula, but with PVD, the cortical vitreousoften develops a second discontinuity called a premacularhole, which may help drugs delivered intravitreally to prefer-entially target the macula.

During sessions 1 and 2 of the SERC 2009, it was shown thatimmediately after intravitreal injection, drugs initially concen-trate near the injection site or in the cisternae described by

Worst over the short-term (8 hours to 2 days), forming vitreousconcentration gradients (Laude A, et al., manuscript submitted)before distributing throughout the entire vitreous cavity andthen reaching steady state equilibrium levels (Lee SS, et al.IOVS 2009;50:ARVO E-Abstract 5950).13 If fluorescein is deliv-ered as a microsphere preparation, the particles delineate theinjection bleb and the diffusion front moves ahead of theretained depot.

W. L. Fowlks14 showed that posterior meridional pararetinalflow occurred in addition to diffusion along the outer 2 mm ofthe vitreous after the injection of India ink into the vitreous ofanesthetized rabbits. The duration of this temporary concen-tration gradient is not affected significantly by head or eyemovement, but it is significantly decreased with age-relatedvitreous syneresis, since drug diffusivity and convection flowincreases, resulting in increased drug distribution and evendrug clearance (Lee SS, et al. IOVS 2009;50:ARVO E-Abstract5950). However, Uday B. Kompella, PhD, showed that withintravitreal fluocinolone acetonide sustained-release devicesthe location of implant placement in the vitreous (anteriorplacement behind lens versus posterior placement near theretina) influences drug levels in various tissues. Specifically,when the implant was placed in the posterior region, druglevels were higher in the posterior retina, choroid-retinal pig-

FIGURE 5. Diagram of common ocular drug delivery methods discussed at the ARVO 2009 Summer Eye Research Conference including variousadjuvant implant devices. Adapted with permission from Lee SS, Robinson MR. Novel drug delivery systems for retinal diseases. Ophthalmic Res.2009;41:124–135. © 2009 S. Karger AG, Basel.


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ment epithelium (RPE), and sclera and lower in the anteriorretina, choroid-RPE, and sclera.

Thus, posterior placement of the implant is likely to supportrelease of the drug to target tissues in case of retinal disorders.It would be beneficial if such posterior placement also reduceddrug levels in lens and trabecular meshwork, tissues associatedwith side effects of corticosteroids. Although the posteriorimplant reduced drug levels in the lens, no such advantage wasfound with respect to corticosteroid levels in the trabecularmeshwork, possibly due to the high affinity of the drug for thistissue. These trends, although apparent at the end of 2 weeks,were more prominent at the end of 4 weeks. These observa-tions are helpful in controlling implant location and, hence,drug targeting.

Kompella thinks that after intravitreal placement of an im-plant, drug levels are not likely to achieve a uniform levelthroughout the vitreous. However, it is probable that a slow-release system achieves zones of steady state concentration,with the contours dictated by the clearance mechanisms of agiven therapeutic agent. The reason for such zones or contoursof steady state concentration is not necessarily diffusion limi-tation, but rather the presence of continuous dynamic clear-ance mechanisms in the posterior segment.

Kay D. Rittenhouse, PhD, added that despite these deliveryplatform–induced concentration gradients, the physiochemicalproperties of the drug are ultimately responsible for efficacyand bioavailability. Once the drug is released into a dissolvingsolution, the drug’s intrinsic properties then dictate the overallefficacy and safety profile. She further elaborated on seeminginconsistencies in rank order of drugs of a similar class orstructure. Data obtained from different preclinical models usedto establish potency profiles for glucocorticoids, for example,have resulted in different outcomes. These outcomes are mostlikely due to the complex relationship between drug aqueoussolubility and lower potency (enhancing ready drug access totissues and rapid clearance from the tissues), versus high-potency drugs with low aqueous solubility and potentially lowsustained concentrations within the eye.

In comparison to the hypocellular vitreous humor, the ret-ina is primarily a cellular central nervous system tissue with 15-to 20-nm wide intercellular spaces that do not contain tightjunctions (TJs).15 Thus, both small hydrophilic and lipophilicdrugs can easily permeate the retina. Drugs with a cationiccharge were found to be the most resistant to permeating theretina, followed by drugs with a large molecular size.16 Thissuggests that vitrectomy does not solve all the drug penetrationproblems, because the drugs also must enter or cross theretina.

Dynamic Physiologic Clearance Mechanisms. Thereare two main mechanisms of drug clearance for intravitreallyadministered drugs in the eye: the anterior elimination path-way via counterdirectional bulk aqueous flow and the poste-rior elimination pathway via vitreoretinochoroidal bulk flowdue to hydrostatic and osmotic pressure gradients in the inner,middle, and outer coats of the posterior segment.7 An addi-tional mechanism to consider is the transcellular carrier–medi-ated transporters found on the RPE. Influx transporters en-hance the penetration of drugs and efflux transporters inhibitretention of drugs across the outer (o)BRB.17

The duration of action of an intravitreally administered drugmay in part depend on the retention of the injected drug at thesite of administration. The longer the intravitreal half-life, thegreater the anticipated duration of therapeutic response (i.e., alonger half-life makes less frequent doses feasible). In general,animal experiments have shown that the half-lives of drugs thatare eliminated through both the retina and the aqueous humor,such as small lipophilic drugs, tend to be shorter than thehalf-lives of drugs eliminated primarily via the anterior route,

such as large hydrophilic drugs. This shorter half-life mayreflect the longer distance and smaller surface area for drugelimination found anteriorly and, secondarily, the transcellularcarrier–mediated transport mechanisms found posteriorly. Lim-ited information has been obtained about the biotransforma-tion or metabolism of exogenously administered small mole-cules within the vitreous and retina. Thus, their impact onclearance mechanisms is generally unknown.

Intravitreal drug elimination also depends on the molecularweight (MW) of the drug, with larger MW (�70,000) drugsdisplaying longer half-lives. Quantitative structure–pharmaco-kinetic relationship approaches attempt to derive relationshipsbetween the physiochemical properties of drugs, such as theMW, lipophilicity, ionic charge, and solubility, and their phar-macokinetic properties, such as the volume of distribution,bioavailability, and duration of action. The quantitative struc-ture–pharmacokinetic relationship between a drug’s physico-chemical properties and elimination in the vitreous was re-cently shown by Kompella et al.,10 who used a logarithmicregression model depending on multiple physiochemical prop-erties, including MW, lipophilicity, and dose number (dose/solubility) of the drug.

One poster presenter, S. Kevin Li, PhD, showed that hecould noninvasively monitor the intravitreal clearance of drugsin vivo by using fluorine magnetic resonance imaging (19FMRI). According to Li, although 19F MRI is a laboratory-basedtechnique and is not currently feasible for use in a clinicalsetting because of its sensitivity and technical difficulties, non-invasive monitoring of the clearance of fluorine-containingdrugs using 19F MR spectroscopy could advance our under-standing of intravitreal clearance mechanisms and eventuallyallow clinicians to maximize their dosage regimens.

Dynamic Physiologic Metabolism. The retina is believedto have the highest metabolic rate per unit weight of any tissuein the body.18,19 Thus, metabolism of essential nutrients suchas glucose, amino acids, and vitamins extensively takes place inthe inner coat (e.g., retina and vitreous humor) of the eye.19

Drug-metabolizing enzymes are also present in many oculartissues, but the ciliary body and the RPE are the most activesites of xenobiotic metabolism in the eye, especially due tocytochrome P-450 and lysosomal enzymes.7 However, theirinfluence is so small in comparison to anatomic permeationbarriers and physiologic clearance mechanisms that they willnot be discussed any further, except in the systemic drugdelivery section, where systemic hepatic metabolism is muchmore pronounced than the local metabolism of the eye.

Adjuvants. As previously mentioned, one means to over-coming the short to medium duration of action of intravitrealdrug solutions is the use of one of several available sustaineddrug release systems. These systems may act through formula-tion modification to decrease the solubility of the drug via asuspension or to enhance the residence time in vitreous humorvia a biodegradable implant, or through the use of a sustained-release delivery device. A review of the currently available orupcoming intravitreal devices was presented by Baruch Kup-permann, MD, PhD (Table 2).20

The Retisert fluocinolone acetonide implant (Bausch &Lomb, Rochester, NY) was the first device of its kind to providesustained delivery of a drug, for the treatment of chronicnoninfectious uveitis affecting the posterior segment of the eyefor up to 3 years. A predecessor implant, Vitrasert (Bausch &Lomb) contains ganciclovir and is indicated for the treatmentof cytomegalovirus (CMV) retinitis. The Vitrasert is larger thanthe Retisert, and implantation therefore requires a larger scleralincision. The evolution of intravitreal devices is toward smallersizes, longer drug release duration, and less-invasive proce-dures, such as being injectable and office-based rather thanrequiring sclerotomies in the operating room.


Kuppermann emphasized that since multiple corticosteroiddelivery devices are relatively effective, the final determinant ofsuccess may be a combination of durability of the effect andsafety issues, such as rates of cataract formation and steroid-induced glaucoma. For example, Retisert has been shown tohave a rate of cataract formation of nearly 100% just 2 to 3 yearsafter placement, and roughly a 40% rate of severe steroid-induced glaucoma that requires surgical intervention. By com-parison, the Ozurdex (Allergan, Inc., Irvine, CA) dexametha-sone implant approved by the U.S. Food and DrugAdministration (FDA) for ME due to retinal vein occlusion lasts3 to 6 months, but has a much lower rate of cataract formationand steroid-induced glaucoma. Study results that became avail-able in December 2009 from a pivotal 2-year trial of the Iluvien(pSivida, Watertown, MA) fluocinolone acetonide implant in956 patients with diabetic macular edema indicated that asystem that delivers lowered rather than higher dosages of thesteroid over 24 months produced the best balance betweensafety and efficacy.

Another highlight of SERC 2009 were two talks given on therecent development of an implantable intravitreal device thatuses genetically modified ARPE-19 RPE cells (transfected withplasmid gene insertion techniques) to release a therapeuticgrowth factor protein, ciliary neurotrophic factor (CNTF), withzero-order kinetics.21,22 Weng Tao, MD, PhD, explained that toavoid immune rejection, the cells are encapsulated within asemipermeable, hollow-fiber membrane, intravitreal implantdevice so that the CNTF protein is released to ocular tissues butthe modified RPE cells are immunologically isolated from thepatient. CNTF is a neurotrophic growth factor with profoundantiapoptotic effects that prolong the lives of dying photorecep-tor cells. Phase 2 trials showed that this delivery system was safe,and a dose-dependent biological effect on the retina was ob-served. Potential visual benefit was also shown in patients withgeographic atrophy.23 The duration of action of this encapsu-lated cell therapy device was found to be up to 2 years.Next-phase clinical trials are under way to continue to evaluateencapsulated cell technology (ECT)-CNTF’s effectiveness forthe treatment of dry AMD and retinitis pigmentosa.

Periocular Drug Delivery Routes

Periocular drug delivery using the transscleral absorption path-way is one of the safest means of achieving consistent thera-peutic drug concentrations in the inner coat of the posteriorsegment (Table 1).5,6,24 Periocular drug delivery systems, how-ever, require drugs to pass through several layers of oculartissue (episclera, sclera, choroid, Bruch’s membrane, and RPE)to reach the retina or vitreous humor.7,25,26 As a result, steepdrug concentration gradients develop, with the highest con-centration developing at the sclera, the lowest concentrationin the vitreous, and the second lowest in the retina. In addition,the clearance mechanisms in the subconjunctival space nearthe limbus appear to be robust, which can affect the amountand retention time of depot drug that is available for absorptiontranssclerally, especially when given via subconjunctival injec-tion (Fig. 5).7,26–28 This clearance mechanism is perhaps lessimportant for drug delivery by sub-Tenon’s injection.25

Although the static anatomic barriers to various perioculardrug delivery techniques have been examined in detail, partic-ularly the sclera, the literature on the contributions of thedynamic clearance mechanisms and the metabolic impedi-ments to various periocular drug delivery techniques unfortu-nately is still lacking.7 Current knowledge shows that thecombined effects of several static anatomic barriers and dy-namic clearance mechanisms generally make periocular drugdelivery one of the least effective ways of attaining high peaktherapeutic intraocular drug concentrations in the retina orT

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vitreous humor (Table 1).5,6 Another reason for this ineffi-ciency is that the posterior transretinal elimination pathwayfrom the vitreous humor occurs in the outward direction.Thus, inward-directed periocular drug delivery goes against thenatural bulk clearance flow in the posterior segment of the eye.

Taken together, these factors result in low intraocular bio-availability of drug delivered by the various periocular drugtechniques, compared with that of intravitreal injection (Table1). However, the periocular route does seem to achieve betterbioavailability in the outer and middle coats of the eye. Thepresence of several clearance mechanisms, as alluded to ear-lier, which are not found with intravitreal injection, also causeperiocular drug delivery to have a shorter duration of actionthan intravitreal injection (Table 1).7,25,26 This route has beenmade a more viable competitor with intravitreal injection bypartially alleviating the latter disadvantage through formulationmodifications and drug device development.

Overall, when the safety and efficacy of this drug deliveryroute is compared with that of the others for the treatment ofdisease in the inner coat of the posterior segment (Table 1),periocular injection is one of the best for safety, and it is in themiddle to low end for efficacy, after intrinsic drug propertiesare factored in, such as potency and exposure–response rela-tionships. It appears that it is ideally suited as a treatmentoption for mild to moderate acute posterior segment disease orfor preventative drug therapy. For serious acute posterior seg-ment diseases or chronic or recurrent diseases, periocularinjection is best used as a supplement to other delivery routes.In contrast, for diseases of the middle (e.g., uveal tract) andouter coats (e.g., sclera and cornea) of the eye, this route ofdrug delivery is currently one of the most preferred, largelybecause of the higher drug exposure to the target tissues.

With a few modifications, this route has the greatest poten-tial to surpass intravitreal injection as the preferred treatmentoption for disease of the inner coat of the eye, since it depositsdrug locally immediately adjacent to the targeted tissue with-out being overly invasive. A formulation or device with zero- orfirst-order sustained-release kinetics may be the most promis-ing research area that could supplant intravitreal injection asthe preferred drug delivery route and relieve clinicians of thetreatment burden of cumulative injection-related complica-tions.

Static Anatomic Permeability Barriers. The static ana-tomic barriers of sub-Tenon drug injection are the sclera, cho-roid, and RPE.25,29 The sclera is a soft connective tissue con-sisting of 68% water, with the remainder composed ofcollagen, proteoglycans, fibrocyte constituents, elastin, bloodvessel constituents, and other substances.30 It therefore actsmore like a sponge and a possible depot reservoir site than asa true barrier. The thickness of the sclera varies in differentparts of the globe from 0.3 to 1.0 mm, typically being thinnestunder the rectus muscle insertion sites or at the equator andbeing thickest posteriorly near the optic nerve.31 It is alsoperforated by numerous arteries, veins, and nerves, whichagain lowers the possibility of any significant barrier effects.

For large or hydrophilic drugs, the RPE (oBRB) has beenfound to be 10- to 100-times less permeable than the sclera and14 to 16 times less permeable than the choroid–Bruch’s mem-brane complex, whereas for small lipophilic drugs, the RPE,choroid–Bruch’s membrane complex, and sclera are relativelyequal barriers.32 Molecules that can passively diffuse across theRPE, whether by transcellular or paracellular pathways, showsimilar permeability values in the outward (retina-to-choroid)and inward (choroid-to-retina) directions, whereas moleculesthat are actively transported across the RPE via transcellularcarrier–mediated transporters show differences in permeabilitybetween the two directions.16,33

The transscleral clearance mechanisms (discussed later)may also have an inhibitory role on transscleral drug perme-ation if the drug depot amount (volume and concentration)and scleral surface area of exposure is less than the saturationrate of the clearance mechanisms, particularly the subconjunc-tival–episcleral lymphatic and blood vessel clearance mecha-nisms.7 In addition, small, lipophilic, and/or cationic drugs maybind to melanin (acidic and polyanionic polymeric pigmentedcompounds) in the RPE or choroid, thereby reducing theirpermeation.34,35 Eumelanin is found in the pigmented melano-cytes of the uvea and in melanosomes of RPE cells, both ofwhich modify the pharmacokinetics and duration of action ofthese drugs at the cellular level, since less peak free drug isavailable, but more is released in a slower, sustained manner.34

The affinity for melanin correlates positively with the lipophi-licity, alkalinity, or cationic charge of the drug being applied.36

Overall, the rate-limiting factors for posterior segment drugdelivery using the periocular drug delivery route depends onthe individual physiochemical properties of the drug itself—predominantly the molecular radius (�8 nm molecular radiidrugs) and the lipophilicity of the drug, and, secondarily, theshape, MW, protein and melanin binding properties, and ioniccharge of the drug.25,30,35

Dynamic Physiologic Clearance Mechanisms. Whenthe clearance mechanisms of sub-Tenon’s injection are comparedto intravitreal injection, substances delivered by the sub-Tenon’sroute are dynamically eliminated from ocular tissues throughsubconjunctival–episcleral blood and lymph vessel flow (�5%–80% drug removal rate) and choriocapillaris blood flow (�2%–20% drug removal rate).5,24,25 The subconjunctival–episcleralclearance mechanism is composed of four separate vascularplexi: superficial subconjunctival plexus (found below the ep-ithelium), deep subconjunctival plexus (found within Tenon’sfascia but just above the episclera), superficial episcleral plexus(found in the most superficial episclera), and deep episcleralplexi (found in the deepest episclera). All four plexi are mostprominent along a 4-mm zone anterior to the rectus muscleinsertion sites, whereas they are markedly less vascular poste-riorly. These vascular plexi contain nonfenestrated endotheliawith 20-nm intercellular spaces and no TJs.26,30 Whereas theepisclera and sclera are devoid of lymphatic plexi, the conjunc-tiva has two prominent subconjunctival lymphatic plexi, thesuperficial and deep subconjunctival, which run in tandemwith the two vascular ones.26

Sustained-release drug depots with release rates that exceedthe innate saturable clearance rates will deliver drugs transs-clerally into the retina and vitreous.37 Thus, estimating thiscutoff point is important when developing sustained-releasedrug formulations or devices for placement in the sub-Tenon’sspace.27,28 The excellent subconjunctival–episcleral clearancemechanism best explains why the first-order kinetics of devicesthat permit the sustained release of drugs rapidly becomessmaller over time as the drug release rate from the depoteventually falls below the saturation point required to over-come the clearance mechanisms. Note that clearance rates varyaccording to the specific physiochemical properties of eachspecific drug being injected or implanted. Uptake by the rapidblood flow of the choroid is another mechanism by whichdrugs can be eliminated, but it has not been studied as well asthe subconjunctival–episcleral clearance mechanism.

Adjuvants. A major adjuvant used to overcome the short tomedium duration of action of periocular drug solutions is thedevelopment of several sustained drug release systems,whether through formulation modifications or through varioussustained release drug delivery devices. Many of these innova-tive options have been discussed and published previously,and include liposomes, microspheres, nanoparticles, and bio-degradable fibrin sealants.5


Some new ideas on this topic discussed at SERC 2009 wereincluded in a review by Thierry Nivaggoli, PhD, on how drugformulation of the immunomodulatory drug sirolimus (rapamy-cin; an inhibitor of the mammalian target of rapamycin) couldsignificantly enhance its duration of action when given bysubconjunctival injection. By altering the formulation of thisdrug from an aqueous solution to a nonaqueous suspension(lowering its MW and solubility, and increasing its lipophilic-ity) and by increasing its depot concentration, Nivaggolishowed they could increase the duration of action from 2 to 6months after a single subconjunctival injection.

Another innovative strategy discussed was the conversionof episcleral depot drug solutions to a solid form, as with atissue tablet. Ashkan Khalili, MD, summarized his work withcolleagues at the Moorfields Eye Hospital on developing atissue tablet of bevacizumab that, when placed in the subcon-junctival space, could increase the duration of action of theantibody to vascular endothelial growth factor (VEGF) from 2hours to 6 days (Khalili A, et al. IOVS 2009;50:ARVO E-Abstract5992).

Another possibility was presented in the poster session byRichard Eiferman, MD, who reported that he could extend theduration of action of dexamethasone from 2 weeks to nearly 6months by placing an impermeable backing on a collagenwafer and inserting it in the sub-Tenon’s space.38 This createsunidirectional transscleral diffusion into the posterior segment.

One of the highlights of the meeting was a presentation ona new innovative sealed drug depot reservoir by Murphree,from the Vision Center at Childrens Hospital in Los Angeles.39

The episcleral drug reservoir is an impermeable silicone exo-plant, which prevents washout by the subconjunctival–epi-scleral clearance mechanism and enhances net unidirectionaltransscleral drug delivery to retina and vitreous.

According to Murphree, experiments using sodium fluores-cein showed that containment in the episcleral drug reservoirincreased intravitreal bioavailability by 30- to 40-fold and theduration of action by 21-fold compared to standard sub-Tenon’s injection.40 He also mentioned that effective trans-scleral delivery of chemotherapeutic agents, such as carbopla-tin and topotecan, has been demonstrated and that biopeptidesas large as bevacizumab (160 kDa) can be successfully deliv-ered using this system.

Murphree and the company developing the system, 3TOphthalmics, have received NCI Rapid Access to InterventionDevelopment (RAID) funding for their Investigational NewDrugs (IND) application. This funding will cover the clinicalsupplies necessary to begin phase 1 and 2 clinical trials withsustained-release formulations of both carboplatin and topote-can for salvage therapy of eyes with retinoblastoma. Thesestudies should begin in the spring or summer of 2010. He alsomentioned that this device could be used for drugs in bothliquid and solid form and that combination therapies could bedeveloped with either two separate devices or one device withtwo cavities.

Hybrid Drug Delivery

To avoid some of the shortcomings in safety and bioavailabilitywith intravitreal or periocular injection, minimally invasivehollow and solid microneedles (�1 mm diameter) have beendeveloped to deliver drugs into the cornea, sclera, or supra-choroidal space.41 Solid, drug-coated microneedles are used forintracorneal and intrascleral drug delivery, improved bioavail-ability, and duration of action. Hollow microneedles are usedfor intrascleral and suprachoroidal delivery of a sustained-re-lease drug depot in a tissue layer, with clearance mechanismsthat are minimal or less than those in the subconjunctival orsub-Tenon’s space. Microneedles allow for better retinochoroi-

dal targeting than periocular drug delivery, because it is closerto the target tissue.42,43

A hollow microcatheter cannulation drug delivery tech-nique has also been developed for suprachoroidal drug deliv-ery. It is more directly invasive than the hollow microneedleapproach, but microcatheter delivery may be promising forsustained drug delivery if it can be shown that continuousinfusion of drugs into the suprachoroidal space can be toler-ated better than a one-time injection with a microneedle.44

Overall, despite being relatively new and having few long-term data, the hybrid delivery route is arguably the second bestfor safety (tied with periocular and just behind topical) andsecond best for efficacy (the best being intraocular). Thisranking has not been definitively proven in clinical trials. An-other drawback that has not yet been calculated is the greaterexpense associated with this technology.

Static Anatomic Permeability Barriers. The static ana-tomic barriers to suprachoroidal injection are the porous tis-sues of the choroid, interfibrillar spaces in Bruch’s membrane,TJs in the RPE, and the intercellular spaces of the retina. Withintrascleral injection, one must also account for the barrierposed by the sclera (50-nm wide interfibrillar spaces). In sum-mary, the permeation barriers are quite similar to those en-countered with sub-Tenon’s injection, except that the contri-bution of the episclera and all or part of the sclera can besubtracted. An added benefit, as far as injection volumes areconcerned is that the suprachoroidal space can accept volumesup to 0.5 mL, whereas intrascleral injections are limited to 10to 35 �L.45

Dynamic Physiologic Clearance Mechanisms. Themain clearance mechanism to both suprachoroidal and intra-scleral injection is the choriocapillaris blood flow. However,with subconjunctival injection, it was determined that thisclearance mechanism is minor (25% of the clearance rate)when compared with the subconjunctival–episcleral clearancemechanism.7 The circumvention of the subconjunctival–epi-scleral clearance mechanism may be the main reason that, inanimal studies, microneedle hybrid drug delivery techniqueshave produced up to an 80-fold greater intraocular bioavailabil-ity than have periocular drug delivery techniques and a 3-foldlonger duration of action.

Adjuvants. As this drug delivery route has only one majorshortcoming—short to medium duration of action—the mainadjuvant is a sustained drug release system. Several options areavailable: a suprachoroidal microcannulation technique; achange in drug formulations to maximize drug depot retention;an increase of drug binding in the delivered tissues, perhaps tomelanin in melanocytes of the choroid or RPE or to proteogly-cans and collagen in the sclera; and intrascleral implants ordevices.

An innovative idea discussed by Francine Behar-Cohen, MD,PhD, at SERC 2009 was using gene therapy to convert thenormal ciliary muscle into an intraocular bioreactor that se-cretes the desired therapeutic protein.46–48 In studies con-ducted in a rat model of uveitis, she used a microneedle-enabled gene delivery technique to transfect the ciliary musclewith plasmids encoding three different variants of the p55tumor necrosis factor-� soluble receptor. She found that thetransfected ciliary muscle self-produced and release intraocularmonomeric tumor necrosis factor-�–soluble receptors for upto 8 months. She also showed preclinical data that suggest thatthese receptors successfully induced local immunomodulationof experimental intraocular inflammation.

Topical Drug Delivery

Topical instillation of ophthalmic drops is the most commonmethod used to administer pharmaceutical agents for ocular


disease; 90% of ophthalmic drug formulations are for topicaldrop use. Methods of topical drug delivery include eye drops,ointments, suspensions, contact lenses, and some drug deliverydevices. The topical route of administration is preferred formany classes of drugs when treating diseases of the anteriorsegment because of ease of access and patient compliance andbecause drops can easily achieve therapeutic concentrationlevels in anterior segment tissues. The anatomy and physiologyof the eye seem to pose almost insurmountable barriers fortopical drug delivery to the posterior segment tissues, buttopically administered drugs have been shown to reach theback of the eye.2

The barriers to productive topical absorption of drugs intothe anterior chamber are well documented.2 Further posteriormovement via transcorneal absorption is thought to be pre-vented by the iridolenticular diaphragm and the anterior-di-rected aqueous humor bulk flow. In classic studies, DavidMaurice, PhD,49 calculated that topical drugs could reach thevitreous cavity, most likely by either the conjunctival-scleral-choroidal-RPE-retinal route or possibly the conjunctival-orbital-optic nerve head pathway, with an intravitreal bioavailabilityranging from 0.0001% to 0.0004%.

Despite the extremely poor intravitreal and intraretinal bio-availability, the advantages of topical drug delivery for retinaldiseases are quite appealing because it minimizes the chance ofsystemic side effects and is minimally invasive. Overall, if bio-availability can be improved, topical approaches to retinaldisease can be convenient, self-administered, and can lowerthe overall treatment burden for chronic diseases.

Overall, if the specific physiochemical properties of a top-ical drug solution allow it to reach the retina or vitreous attherapeutic concentrations, a topical drug delivery route canbe considered the best for safety and convenience. Currently,because of work in various eye models, it is thought thattopical drug delivery for retinal diseases may be tied for lastalong with systemic delivery when it comes to efficacy. Beforethe topical approach can be considered a viable competitorwith intravitreal injection, most conventional topical drug so-lutions must undergo modification, such as changes in formu-lation or modification for use in adjuvant drug delivery devicesthat will increase conjunctival penetration for better intravit-real and intraretinal bioavailability and, secondarily, greaterresidence time in the conjunctival cul-de-sac for longer dura-tion of action.50

Peter A. Campochiaro, MD, summarized several preclin-ical experiments in mice and clinical trials in which topicallyadministered drugs, such as nepafenac, TG100801,mecamylamine, and pazopanib were used.51–53 These studiesshowed that it is possible to achieve therapeutic effects in thevitreous and retina after topical delivery, in some cases by thetransconjunctival–transscleral pathway. Despite these occa-sional successes, he mentioned that there have been manyfailures. Therefore, it is difficult to predict which drugs canachieve adequate therapeutic levels in the inner coat of theposterior segment after topical drug delivery and whetherpenetration can be enhanced by structural modifications or aparticular formulation. Thus, experimental testing in animalmodels is critical. As the list of drugs that achieve therapeuticlevels in the retina and choroid after topical administrationincreases, it may be possible to identify structural characteris-tics that promote ocular penetration and to specifically designdrugs and/or prodrugs accordingly.

Static Anatomic Permeability Barriers. The static ana-tomic barriers to topical drops are the corneal epithelium,conjunctival epithelium, sclera, choroid, Bruch’s membrane,RPE, and the retina.30,54 The conjunctival epithelium is 55times more permeable than the corneal epithelium and allowsthe passive diffusion of 12-fold larger solutes, primarily because

of the combined affect of the “leaky” goblet cell subpopulationof surface cells and the larger surface area for drug contact(conjunctival surface area is 17 times greater than that of thecornea).

Because the permeability across the RPE is 10 times higherthan that across the conjunctival epithelium, the conjunctiva isthe rate-limiting anatomic barrier to passive paracellular pene-tration into the posterior segment of large and/or hydrophilicdrugs.2 In contrast, for small, lipophilic drugs, the combinedeffects of the RPE and conjunctival epithelium are the rate-limiting anatomic barriers to passive or active transcellularpenetration, primarily due to the xenobiotic efflux carrier-mediated transporter (pumps).

In summary, the permeation barriers to topical drug deliv-ery are most similar to those of subconjunctival injection,except that the effects of the conjunctival epithelium, whichdecreases drug permeation approximately fivefold, must beadded to the effects of the other noted barriers.2,54

Dynamic Physiologic Clearance Mechanisms. Topicaldrops encounter more local clearance mechanisms beforereaching the inner coat of the posterior segment than do drugsdelivered by any other route. At tear turnover rates of 0.5 to 2.2�L/min and removal at 50% to 100%, the lacrimal gland–derived tear clearance mechanism plays a major role in drugclearance from the ocular surface. Topical drop solutions typ-ically remain on the ocular surface for an average of only 5minutes before being washed away by the lacrimal gland-derived tears into the nasolacrimal duct. Drugs that manage topenetrate tissues may be cleared by the subconjunctival–epis-cleral blood and lymph vessel flow and the choriocapillarisblood flow. The cumulative effect of all the clearance mecha-nisms clearly explains the short duration of action of topicaldrug delivery and also partially explains the extremely poorintraretinal and intravitreal bioavailability of most commer-cially available topical drug solutions.

Adjuvants. As this drug delivery route has two major short-comings, extremely poor bioavailability to the inner coat of theposterior segment and a short duration of action, the mainadjuvants are penetration enhancers and sustained-release drugdelivery systems.

Drug development studies indicate that paracellular pene-tration by topical drugs can be improved by several mecha-nisms including: (1) opening TJs by using preservatives intopical medications or by iatrogenic epithelial scraping, (2)increasing drug lipophilicity through the use of prodrugs orother analogues, such as surfactants, and (3) binding the drugsto dendrimers that use carrier-mediated influx transporters.

One promising option presented by Ashim Mitra, PhD, atSERC 2009 involves encapsulating drugs in a biodegradablecarrier with a hydrophilic exterior and a lipophilic interior.Mitra described a novel mixed micellar-based formulation ofLX-214 (Lux Biosciences, Jersey City, NJ)—vitamin E TPGS andoctoxynol-40 polymer—that allowed hydrophobic immuno-suppressant and anti-inflammatory steroid drugs to reach theretina in therapeutic concentrations by permeation throughthe transconjunctival–transscleral pathway. In pharmacoki-netic studies, topical application of a voclosporin preparationreached peak intraretinal and intravitreal bioavailability mea-surements of 0.2% and 0.001%, respectively. According toMitra, the mixed micelle coating, with a hydrophilic exteriorand a hydrophobic interior, helps the drugs evade the clear-ance mechanisms of the eye. An interesting finding was thatthe vitreous humor drug levels for both voclosporin and dexa-methasone were below detectable limits, suggesting that themicelles release the drug in the choroid, just behind the RPE.Mitra noted that the safety and efficacy of this approach will beevaluated in phase 2 and 3 clinical trials soon.55


Mark Kester, PhD, discussed two experimental topical drugdelivery alternatives: nanoliposomes and calcium phosphatenanoparticles, also known as nanojackets.56–61 He describedproof-of-concept studies that explored the potential of subcon-junctival or topical delivery of minocycline or doxycycline inencapsulated nanoliposomes (�80 nm in diameter). The drugscould be used in DR for their matrix metalloproteinase andother anti-inflammatory effects. In addition, he discussed indo-cyanine green–encapsulated nanojackets (�30 nm in diame-ter) for near infrared imaging of posterior segments of the eye.He mentioned that nanoparticles can also be pegylated on theexterior surface to evade the immune system and even toselectively deliver their contents to specific targets.

Two more highlights of the meeting were presentations oniontophoresis given by Jean-Marie Parel, PhD, and Mike Patane,PhD. Iontophoresis is an old technology that has recently beenmodified into a new innovative drug delivery platform. Recentclinical trials have demonstrated that iontophoresis is suffi-ciently safe and capable of delivering steroids to ocular tissueto treat uveitis. Development in iontophoresis may bring thesedevices to the U.S. commercial market by 2011.

Parel discussed the history of iontophoresis in medicine andfollowed by summarizing his experiences since the 1970susing the coulomb-controlled iontophoresis unit for transcor-neal and transscleral drug delivery (Parel JM, et al., manuscriptin preparation).46 Iontophoresis is a noninvasive method ofpropelling charged active compounds (e.g., low MW drugs,high MW biological proteins, and gene therapeutics) into ei-ther the anterior or posterior segment.62 It is performed byapplying a small electrical current that has the same charge asthe drug to create repulsive electromotive forces. He pre-sented several examples of diseases and conditions that hadbeen treated with ionized drugs that were driven into oculartissues by coulomb-controlled iontophoresis to overcome poorocular penetration properties. These included fungal keratitis,uveitis, cytomegalovirus retinitis, retinoblastoma, and prolifer-ative vitreoretinopathy. He also showed how the sclera andcornea act as a drug reservoir or sponge, providing slow,sustained release of drugs to the retina, choroid, or cornea. Healso noted that, after conventional iontophoresis, the drugconcentrations in the vitreous humor, aqueous humor, andlens were almost nil.

An iontophoretic device has been evaluated in phase 2clinical trials for the treatment of dry eye.63 Patane followedParel with a discussion on EyeGate II (Eye Gate Pharma,Waltham, MA). He summarized results of the phase 1 safety andtolerability studies and described how procedures with thedevice could be routinely performed in-office in as few as 1 to4 minutes. Preclinical and clinical studies to date have shownthat iontophoresis can increase intraocular bioavailability over100-fold more than topical drops and is able to increase theduration of action of drugs by more than threefold. Comparedwith past iontophoresis device models, the Eyegate II designspreads the electrical charge over a scleral surface area of 1cm2, which is larger than that of the conventional devicesdescribed by Parel.

Previously published sustained-release formulation modifi-cations and drug release devices such as gels, suspensions,ointments, biomucoadhesives, hydrogel contact lenses, cor-neal collagen shields, and conjunctival cul-de-sac insert de-vices, will not be reviewed. A novel device presented byJoseph Ciolino, MD, in the poster session is a prototype drug-eluting contact lens made of a polymer-drug film encapsulatedwithin a poly-2-hydroxyethyl methacrylate (pHEMA) hydrogel.The release rate of the drug could be modified by changing thecharacteristics of the film’s MW or its polymer-to-drug ratio.The prototype lenses that were made incorporating ciprofloxa-

cin produced drug release with 0-order kinetics up to 4 weeksin duration.64

Kongara Papangkorn, MD, presented a novel topical drugdelivery device composed of a plastic dome that is applied toand sealed on the bulbar conjunctiva. The dome decreaseslacrimal gland–derived tear clearance or washout and, whencombined with formulation adjuvants, such as oxymetazolineor calcium ions, resulted in intraocular drug concentrationsfrom passive diffusion that were comparable to those of ion-tophoresis and markedly higher than standard topical dropapplication (Higuchi JW, et al. IOVS 2009;50:ARVO E-Abstract5996; Papangkorn K, et al. 2009;50:ARVO E-Abstract 5318)65

For example, experiments with rabbits that were treated withdexamethasone sodium phosphate resulted in an intraretinalbioavailability of 4% and an intravitreal bioavailability of 1%.Based on the results of these experiments, Papangkorn rea-soned that three major factors influence passive topical drugdiffusion to the posterior segment tissues: (1) the contactsurface area of the drug, (2) the contact time of the drug on theeye surface, and (3) the concentration of the drug in theapplicator. By using their unique topical drug delivery devicecombined with oxymetazoline or Ca2�, they hope to deliverdrugs noninvasively into the inner coat of the posterior seg-ment with a brief treatment period of 5 to 20 minutes.

Systemic Drug Delivery Routes

Systemic penetration of many drugs, particularly large or hy-drophilic ones, into the posterior segment of the eye is re-stricted by the BRB. For example, fluorescein transverses thechoriocapillaris and penetrates the choroid in a matter ofminutes as the choroidal tissue rapidly equilibrates with theblood. Further movement from the choroid into internal ocularstructures such as the retina and vitreous humor, especially oflarge and/or hydrophilic drugs, is restricted by the RPE (oBRB)and TJs of the retinal vasculature (iBRB). Small lipophilic drugs,however, can penetrate the oBRB and iBRB, achieving appre-ciable concentrations in the retina and vitreous humor aftersystemic administration.

The dilution effect of the systemic blood volume (largevolume of distribution) creates the need to use larger doses ofdrugs when they are administered systemically rather than in alocal injection, to yield a sufficient concentration gradient inthe choroid and retina. This need for a larger dose is true evenfor small, lipophilic drugs.2 Also, because of the rapid bloodflow rate in the choroid and retinal vasculature, the duration ofaction of the drug is usually too brief to result in meaningfultherapeutic effects.

Overcoming all these shortcomings necessitates large, con-tinuous systemic drug infusions. These are often associatedwith significant systemic side effects or toxicities, some quiteserious. Since passive and active transcellular transport mech-anisms are present in the RPE and because small, lipophilicdrugs seem to have little trouble in crossing the BRB, somedrugs with specific physiochemical properties, with or with-out carrier molecules, may take advantage of these pathways tobypass the selective passive paracellular diffusion barrier posedby the BRB; however, the problem of their extremely shortduration of action remains unresolved.

Overall, the efficacy of systemic drug delivery to the poste-rior segment of the eye is extremely low—tied for last withtopical drops—and its safety rating is poor due to the potentialrisk of systemic side effects and toxicities.

Static Anatomic Permeability Barriers. The primarystatic anatomic barriers to oral medications are the choriocap-illaris, Bruch’s membrane, the RPE, and the retina, as well asthe well-known problems in absorption from the gastrointes-tinal tract of oral drugs.30 Because systemic blood flow from


the ophthalmic artery also supplies the optic nerve via theshort posterior ciliary arteries, some leakage may occur intothe vitreous cavity or retina due to defects in the blood–opticnerve barrier at the level of the prelaminar optic nervehead.66,67

In summary, the permeation barriers are most similar tothose seen with suprachoroidal hybrid delivery techniques,except that systemic volume effects and rapid ocular bloodflow must be accounted for, in addition to the effects of oraldrug delivery on the gastrointestinal tract.

Dynamic Physiologic Volume of Distribution, Clear-ance, and Metabolic Mechanisms. There are several majorphysiologic barriers to oral delivery of a drug to the eye. Oneis the volume of distribution of the drug—that is, the amountof drug in the body divided by the concentration in the blood.Thus, the oral route has a substantial diluting effect on theapplied original drug concentration. In addition, oral medica-tions have high systemic clearance rates due to first-pass clear-ance and metabolism in the liver and short exposure times inthe choroid and retinal vasculature due to the rapid flow rate inthe systemic bloodstream and choroid.

The blood flow in the human choroid is the highest in theentire human body per gram of tissue (higher than in thecortex of the kidney). More than 70% of all the blood in the eyeis found in the choroid nearest the retina, probably to accom-modate the mitochondrial-rich photoreceptors of the retina,which have the highest metabolic rate and demands for oxy-gen and nutrients per gram of tissue of all cells in the humanbody. In the entire retinal layer, oxygen consumption is 1.5times greater than that of the kidney, 3 times greater than thatof the cerebral cortex, and 6 times greater than that of thecardiac muscle.19,68–70 Because the impinging light is con-verted largely into heat, the retina must have a very effectivecooling system, again provided by the rapid choroidal bloodflow that serves to conduct away the heat produced by absorp-tion of light in the retina and adjacent ocular tissues. Finally,once all these systemic factors are accounted for, there areseveral dynamic local elimination pathways, such as the cho-riocapillaris or retina clearance mechanism and the transcellu-lar xenobiotic efflux transporters of the RPE.

In summary, the combination of the systemic volume ofdistribution, the fast systemic and choroidal blood flow rates,hepatic clearance mechanisms, and smaller local clearancemechanisms result in this delivery route’s brief duration ofaction. The net effect is low to medium bioavailability to theretina and vitreous, depending on whether the drug’s physio-chemical properties allow it to cross the BRB easily.

Adjuvants. Most systemic drugs are formulated with ex-cipients that help overcome their tendency toward a briefduration of action and poor to medium bioavailability to theinner coat of the posterior segment. One novel scheme toenhance the bioavailability of systemic drugs to the retina arepenetration enhancers that help reversibly open up the BRB orimprove transcellular penetration. Because TJ proteins are notvery antigenic, it is difficult to develop antibodies against theirextracellular domain, a fact that has severely hampered thedevelopment of TJ modulators.

At SERC 2009, Matthew Campbell, BSc, discussed a newexperimental treatment option along these lines that employssmall interfering (si)RNA technology to block claudin-5 andreversibly open rabbit inner-BRB TJs.71 Experiments in hislaboratory have shown that intravenously administered clau-din-5 siRNA transiently opened the inner BRB TJs to small MW(�750) tracers for 1 to 2 days. He mentioned that there areseveral other ways to deliver molecules to suppress claudin-5,and their recent work used short hairpin RNA delivered byadenoassociated virus.

Another novel approach to treat retinal disease by systemicdrug delivery was discussed by V. Michael Holers, MD, andBarbel Rohrer, PhD. Holers reviewed the role of the comple-ment pathway in the pathogenesis of ARMD and describedhow dysregulation of the alternate complement pathway, es-pecially in the C3 amplification loop, may be a reasonabletarget for treating AMD and inflammatory retinal diseases byadministering the intravenous fusion protein complement re-ceptor 2 and factor H (CR2-fH), to recognize and inhibit com-plement-activation products.72–74 Complement receptor 2 rec-ognizes C3d, a tissue-bound activation product of complement-mediated inflammation (e.g., drusen), whereas the fH componentof the fusion molecule is the most potent inhibitor of the alterna-tive complement pathway.

Rohrer discussed animal experiments that show that oxida-tive stress sensitizes RPE cells to complement-mediated attackby decreasing regulatory cell surface membrane-bound com-plement inhibitors to the alternative pathway. This sensitiza-tion was further compounded by the fact that oxidative stressalso alters RPE cells in such a way that soluble fH in the serumis less functionally protective.75 Complement-mediated attackof the RPE then results in sublytic activation of the membraneattack complex resulting in vascular endothelial growth factorVEGF release and breakdown of the oBRB.75 In humans, thiscascade of events can result in either dry geographic atrophyor wet AMD. Rohrer concluded with evidence from severalpreclinical studies showing that systemic CR2-fH therapy pro-tects the retina using experimental mouse models of retinaldegeneration and choroidal neovascularization.

MAKING THE TRANSITION FROM BENCH TO BEDSIDE

Currently, the medical treatment of vitreoretinal disease islimited because it is difficult to deliver pharmacologically ac-tive levels of drugs to these tissues for extended periods oftime. Injection of drugs in the sub-Tenon’s space avoids therisks of intravitreal injections, but many drugs cannot be effec-tively delivered to the back of the eye. Intravitreal injectionscan successfully deliver drugs to the retina, but the need formultiple injections increases both risk and treatment burden.Because of the short to medium duration of actions with eitherdrug delivery route, there is an unmet need for safe, effective,controlled, sustained-release ocular delivery systems.

Several approaches are being studied to improve drug de-livery to the back of the eye. Microneedles show great promisein balancing safety and efficacy, and this technology should beexplored and more fully developed. Also, although neither thetopical nor the systemic route to the posterior segment is anefficient pathway for delivering many drugs to the vitreous andretina, recent evidence suggests that these routes should notbe completely abandoned, especially since systemic and topi-cal formulations allow self-administered treatments at homeand thereby lessen the clinical burden that ophthalmologistsface when treating chronic age-related diseases of the eye.

To translate some of the experimental approaches de-scribed at SERC 2009 to effective research and developmentefforts a teamwork-based multidisciplinary approach is neces-sary, combining expertise from several areas, including bioma-terials, bioengineering, pharmacology, toxicology, and clinicalophthalmology. In many cases, this teamwork approach hasalready been used, and the next step to disseminating thisexpertise in science into medical therapy involves know-howin clinical trial design to help identify appropriate humandisease targets, acceptable clinical endpoints or biomarkers,and test populations. Collaborations between scientists in aca-demia, physicians in the clinic, and professionals in industryare essential for bridging the gap from the bench to the com-


mercial market. SERC 2009 also explored the practical steps intranslational medicine as discoveries at the laboratory benchare translated to the bedside. The remainder of this summarywill present themes of translational research, not necessarily inthe order of their presentation at the conference.

Use of Patents to Protect Research

It is important that translational researchers understand howpatents are used to protect inventions and intellectual propertyfrom being used, made, or sold by others for up to 20 years.

Phillip Reilly, JD, PhD, discussed the relevant policies in theUnited States regarding the regulation of utility patents for drugdelivery. He explained that inventors must demonstrate thatthe subjects of their patents are useful, novel, and nonobvious.The criteria for utility can be subjective in some cases, butthose for novelty and nonobviousness have induced height-ened regulation of drug delivery patents. In these cases, patentoffices rely on the recorded dates of seminal inventions, theorder of claims presented, and prior art or relevant research inthe same field as the patent application to satisfy criteria fornonobviousness and novelty.

Adequate knowledge of the scope of an invention, gainedthrough literature searches or practical experience, is impor-tant in the defense of intellectual property. The claims are themost important part of a drug patent; these define the scope ofan invention and defend it against encroachment by others bydelineating and excluding areas of applicability. Reilly cau-tioned that loss of protection for an adequately describedinvention can occur if scientists and clinicians share theirresults with others or make them public before adequate mea-sures are taken to file patents.

Additional impediments to patent security include lack of,or inadequate, laboratory notebook records and failure to un-derstand the scope of prior art. Although patents grant protec-tion for an idea, they do not automatically grant the right topractice an invention. With drugs and drug delivery systems,this right is granted by regulatory agencies such as the FDAthrough the process of clinical trials.

Effective Conduct of Clinical Trials

Emily Chew, MD, focused on the steps involved in progressingfrom early pilot studies (phase 1 and 2) to larger phase 3 trials.She emphasized the importance of the early pilot studies inproviding useful data and in vetting drug candidates for largerphase 2 and 3 trials. Her examples included early-phase studiesperformed with ocular von Hippel-Lindau disease and AMD.

Curtis Meinert, PhD, discussed some common pitfalls inclinical trial design and described how a multidisciplinary teamcan successfully design and conduct a clinical trial. Meinertidentified three common design pitfalls: (1) the absence ofrandomization in the study, (2) using too small a sample size,and (3) lack of sufficient follow-up time in clinical studies.Other design pitfalls included using historical controls as thecomparison group, using unapproved surrogate outcome mea-sures to reduce sample size requirements, and failing to pro-vide sample size calculations.

Meinert concluded by summarizing some obstacles to suc-cessful clinical trials that occur at different levels of planning,such as issues regarding organization (e.g., no governancestructure, no coordinating center, no monitoring body, andnonfunctional clinics), operations (e.g., basing the decision tofollow-up on treatment status, open treatment assignmentschemes, allowing the baseline period to extend beyond themoment of randomization, randomization without checkingeligibility, and no performance monitoring), data analysis (e.g.,analysis by treatment administered, overemphasis of P values,dredged results, and changing the outcome measure post hoc),

publications (e.g., lack of publication, use of ghostwriters, useof nonindexed journals, and premature presentations of data).In the process of translational medicine, clinical trials expertiseis needed to avoid the pitfalls specific to ocular drug deliverysystems.

Karl Csaky, MD, PhD, discussed the appropriate endpointsfor clinical trials in DR, dry AMD, branch retinal vein occlusion,and wet AMD. Extensive papers authored by various studygroups for each of these have been published and will not bediscussed here.76–78 Csaky emphasized that many drug formu-lations are not optimized for ophthalmic drug delivery, andneed to be adapted for use in an existing or developing drugdelivery system. He concluded that after the thorough evalua-tion of clinical trial data, the process continues with the refine-ment of drug delivery methods, which may involve input fromthe FDA as well as involvement from the Centers for Devicesand Radiologic Health.

Future Directions for Basic andTranslational Research

Throughout SERC 2009, participants discussed several areas inwhich they think basic science research and clinical studies inophthalmic drug delivery should be focused for the purpose offostering successful translational research. Six were identified:

1. A better understanding must be developed of the natureand effect of dynamic physiologic processes of the eye,such as clearance mechanisms and metabolism of drugsin specific tissue layers. It was noted that the challengeof isolating the dynamic barriers during data acquisitioncurrently prevents the direct comparison of one dy-namic barrier to another. It was repeatedly emphasizedthat an understanding of the importance of each dy-namic barrier is key to improving the design of currentdrug delivery systems. In addition, it was stressed duringthe conference that live animal model studies or nonin-vasive studies on live human subjects are needed, as exvivo work may not fully address relevant live dynamicphysiologic processes.

2. Each static anatomic barrier encountered for each spe-cific drug delivery technique must be studied, so that allindividual layers of tissue or ocular fluid cavities aremore fully understood. For example, with periocularinjection techniques, the permeability properties of thechoroid, RPE, retina, and vitreous should be individuallyassessed and compared to existing data from studies onthe sclera and Bruch’s membrane.

3. Drug–protein or drug–pigment binding must be bettercharacterized, to guide attempts to modify natural sus-tained-release mechanisms for drug delivery to the pos-terior segment.

4. More research is needed in formulation modificationsthat alter physicochemical properties of both new andold drugs in ways that facilitate delivery through knownparacellular and transcellular pathways. Although theparacellular and transcellular passive diffusion pathwaysoffer an advantage, in that one drug delivery method maybe generalized to various drugs, the active transcellularcarrier–mediated transporters across the BRB should befurther studied as they permit site-specific targetingwithout the need to create transmembrane concentra-tion gradients and aid in tissue-specific targeting.

5. Ophthalmic drug delivery via nanotechnology-basedproducts (�1 �m in diameter) must be further explored,as it fulfills three crucial criteria of ophthalmic drugdelivery by enhancing drug permeation, controlled drugrelease, and selective drug targeting.


6. Innovation and development of ophthalmic gene deliv-ery deserve further study, given the extensive potentialof this technology.

CONCLUSIONS AND AN ACTION PLAN FOR

ADVANCING TRANSLATIONAL RESEARCH IN

OPHTHALMIC DRUG DELIVERY

Effective treatment of posterior segment ophthalmic diseases isa formidable challenge for scientists and clinicians in the oph-thalmic pharmaceutical field. The challenges include the ana-tomic and physiologic barriers that can impede pharmacolog-ically active levels of drug from reaching the targeted tissuesinside the eye, immune reactions and clearance mechanisms tocertain drugs and drug delivery materials, and the often irre-versible nature of vision loss.

Although it was not one of the goals of this conference, anaction plan to sustain future innovations and success in theclinic is needed to marshal the growing interest in this topic, asdemonstrated by the attendance of scientists and cliniciansfrom the pharmaceutical engineering, medical, and academicsectors. To maintain these discussions and see the successfulapplication of more drug delivery systems in ophthalmology,we propose:

● Improved cooperation between basic and applied sci-ence teams at academic institutions, where many novel drugdelivery systems are discovered.

● Cooperation between pharmaceutical companies and ba-sic and applied science investigators, to facilitate the transfer oftechnology, which will enable the development and commer-cialization of novel products.

● Uniform techniques for obtaining ocular tissue samplesfor comparative pharmacokinetic studies. Samples of posteriorocular tissues—including neuroretina (macula and peripheralretina), retinal pigment epithelium, choroid, and sclera—should be obtained in a consistent fashion, to improve datacomparison.

● Clear guidance, including early and frequent communica-tion with regulatory agencies, to help sponsors select theappropriate path to regulatory approval of novel ocular drugdelivery products.

● Meetings and societies that accommodate discourseamong basic, applied, and clinical researchers to help promotefuture collaborative activities in device and drug developmentand ophthalmic translational research.

● Incentives for individuals and institutions that use a teamscience approach to train scientists and physicians to usetranslational strategies for problem-solving in ophthalmology.

● Journals that, by encouraging and accepting translationalresearch papers in such areas as preclinical testing results,development of analytical methods, strategies that enable de-velopment of investigational drugs, and critical analysis of trialsthat do not meet their endpoints, provide researchers with anoutlet to publish translational work.

The application of technological advances in vision scienceis progressing at a rapid rate. Advances in nanotechnology,gene therapy, and biomaterials, for example, hold promise forproviding new solutions to the challenge of ocular drug deliv-ery. To facilitate collaboration among scientists and compa-nies, many universities have established technology transferoffices that provide the researcher with legal advice and thetools to deal with patent protection and contract writing.Scientists who have a better understanding of mechanisms thatfacilitate collaborative research will play key roles in the effec-tive development of new drug delivery methods.

The ultimate goal is to design drugs and delivery devicesthat can more effectively target disease. Greater knowledge ofdrug pharmacokinetics in both normal and diseased oculartissue would greatly hasten further developments in the field.

Acknowledgments

The authors thank the Association for Research in Vision and Ophthal-mology and the National Eye Institute for their support of SERC 2009,Rhonda Williams at ARVO for her dedicated and tireless managementof the project, and Thea Gray for editing the manuscript.

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Ophthalmic Drug Delivery Systems